Translational aspects of pharmacological research into anxiety disorders: The stress-induced hyperthermia (SIH) paradigm

Vinkers, Christiaan H.; Bogaert, Meg J.V. van; Klanker, Marianne; Korte, S. Mechiel; Oosting, Ronald S.; Hanania, Taleen; Hopkins, Seth C.; Olivier, Berend; Groenink, Lucianne

doi:10.1016/j.ejphar.2008.02.097

Cited by 91 publications

(76 citation statements)

References 249 publications

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“…This process is conserved across mammalian species, including rodents and humans. Measurement of the hypothermic response generated subsequent to stressful stimuli represents a translationally valid and useful approach to modelling anxiety disorders (Bouwknecht et al, 2007;Vinkers et al, 2008). The hypothermic response to stress can be attenuated using benzodiazepines, as well as buspirone and ethanol (Spooren et al, 2002), and chronic, but not acute, SSRI treatment (Conley and Hutson, 2007).…”

Section: Sihmentioning

confidence: 99%

The age of anxiety: role of animal models of anxiolytic action in drug discovery

Cryan¹,

Sweeney²

2011

British J Pharmacology

237

188

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Anxiety disorders are common, serious and a growing health problem worldwide. However, the causative factors, aetiology and underlying mechanisms of anxiety disorders, as for most psychiatric disorders, remain relatively poorly understood. Animal models are an important aid in giving insight into the aetiology, neurobiology and, ultimately, the therapy of human anxiety disorders. The approach, however, is challenged with a number of complexities. In particular, the heterogeneous nature of anxiety disorders in humans coupled with the associated multifaceted and descriptive diagnostic criteria, creates challenges in both animal modelling and in clinical research. In this paper, we describe some of the more widely used approaches for assessing the anxiolytic activity of known and potential therapeutic agents. These include ethological, conflict-based, hyponeophagia, vocalization-based, physiological and cognitive-based paradigms. Developments in the characterization of translational models are also summarized, as are the challenges facing researchers in their drug discovery efforts in developing new anxiolytic drugs, not least the ever-shifting clinical conceptualization of anxiety disorders. In conclusion, to date, although animal models of anxiety have relatively good validity, anxiolytic drugs with novel mechanisms have been slow to emerge. It is clear that a better alignment of the interactions between basic and clinical scientists is needed if this is to change.

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Section: Sihmentioning

confidence: 99%

The age of anxiety: role of animal models of anxiolytic action in drug discovery

Cryan¹,

Sweeney²

2011

British J Pharmacology

237

188

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“…Activation of the autonomic nervous system in response to stress, such as exposure to noise, heat, or pain, in animals can be measured by changes in body temperature-a process referred to as stress-induced hyperthermia (SIH). SIH is a short-lasting body temperature elevation (DT) that can be reduced or even ablated by anxiolytic drugs (Vinkers et al, 2008). Basal body temperature measured before compound application did not differ between control and compound-treated mice (data not shown).…”

Section: Ac-sm Shifts the Gaba Concentration-responsementioning

confidence: 93%

A Cycloartane Glycoside Derived from Actaea racemosa L. Modulates GABA_A Receptors and Induces Pronounced Sedation in Mice

Strommer¹,

Khom²,

Kastenberger³

et al. 2014

J Pharmacol Exp Ther

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23-O-Acetylshengmanol 3-O-b-D-xylopyranoside (Ac-SM) isolated from Actaea racemosa L.-an herbal remedy for the treatment of mild menopausal disorders-has been recently identified as a novel efficacious modulator of GABA A receptors composed of a 1 -, b 2 -, and g 2S -subunits. In the present study, we analyzed a potential subunit-selective modulation of GABAinduced chloride currents (I GABA ) at GABA concentrations eliciting 3-8% of the maximal GABA response (EC 3-8 ) through nine GABA A receptor isoforms expressed in Xenopus laevis oocytes by Ac-SM with two-microelectrode voltage clamp and behavioral effects 30 minutes after intraperitoneal application in a mouse model. Efficacy of I GABA enhancement by Ac-SM displayed a mild a-subunit dependence with a 2 b 2 g 2S (maximal I GABA potentiation [E max ] 5 1454 6 97%) and a 5 b 2 g 2S (E max 5 1408 6 87%) receptors being most efficaciously modulated, followed by slightly weaker I GABA enhancement through a 1 b 2 g 2S (E max 5 1187 6 166%) , a 3 b 2 g 2S (E max 5 1174 6 218%), and a 6 b 2 g 2S (E max 5 1171 6 274%) receptors and less pronounced effects on receptors composed of a 4 b 2 g 2S (E max 5 752 6 53%) subunits, whereas potency was not affected by the subunit composition (EC 50 values ranging from a 1 b 2 g 2S 5 35.4 6 12.3 mM to a 5 b 2 g 2S 5 50.9 6 11.8 mM). Replacing b 2 -with b 1 -or b 3 -subunits as well as omitting the g 2S -subunit affected neither efficacy nor potency of I GABA enhancement by Ac-SM. Ac-SM shifted the GABA concentration-response curve toward higher GABA sensitivity (about 3-fold) and significantly increased the maximal GABA response by 44 6 13%, indicating a pharmacological profile distinct from a pure allosteric GABA A receptor modulator. In mice, Ac-SM significantly reduced anxiety-related behavior in the elevated plus maze test at a dose of 0.6 mg/kg, total ambulation in the open field test at doses $6 mg/kg, stressinduced hyperthermia at doses $0.6 mg/kg, and significantly elevated seizure threshold at doses $20 mg/kg body weight. High efficacy and long biologic half-life of Ac-SM suggest that potential cumulative sedative side effects upon repetitive intake of A. racemosa L. preparations might not be negligible.

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“…5). There is evidence that stress-induced hyperthermia is associated with the level of anxiety 1) and that SART-stressed animals have elevated anxiety levels. 31,32) Nonetheless, the anxiolytic, diazepam, failed to reduce the enhanced hyperthermic responses to acute restraint stress in SART-stressed mice, suggesting that the increased anxiety levels are not involved in the increased hyperthermic responses.…”

Section: Discussionmentioning

confidence: 99%

“…[13][14][15] It is hypothesized that stress-induced hyperthermia and infectioninduced fever are two distinct processes mediated largely by different neurobiological mechanisms, 4) although they result in similar clinical signs, i.e., higher body temperature accompanied by shivering and cutaneous vasoconstriction. 1) On the other hand, the influence of chronic or long-term stress on thermoregulation still remains largely unknown. This should be investigated, since chronic stress, rather than acute stress, has great impact on the development of various diseases including neurodegenerative, mental, cardiovascular and gastrointestinal diseases.…”

mentioning

confidence: 99%

“…Apart from infectious fever resulting from activation of the immune system, there exists stress-induced hyperthermia that is often referred to as 'emotional fever.' 1,2) A variety of stresses including psychological stress raise body temperature in mammals, such as rats, 3,4) mice [5][6][7] and humans. [8][9][10][11][12] The acute stress-induced rise in body temperature appears to involve the excitation of the sympathetic nervous system which regulates non-shivering thermogenesis in brown adipose tissue.…”

mentioning

confidence: 99%

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Repeated Cold Stress Enhances the Acute Restraint Stress-Induced Hyperthermia in Mice

Miyamoto

Funakami

Kawashita

et al. 2017

Biological & Pharmaceutical Bulletin

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The rodents exposed to repeated cold stress according to a specific schedule, known as specific alternation of rhythm in temperature (SART), exhibit autonomic imbalance, and is now used as an experimental model of fibromyalgia. To explore the susceptibility of SART-stressed animals to novel acute stress, we tested whether exposure of mice to SART stress for 1 week alters the extent of acute restraint stress-induced hyperthermia. Mice were subjected to 7-d SART stress sessions; i.e., the mice were alternately exposed to 24 and 4°C at 1-h intervals during the daytime (09:00-16:00) and kept at 4°C overnight (16:00-09:00). SARTstressed and unstressed mice were exposed to acute restraint stress for 20-60 min, during which rectal temperature was monitored. Serum corticosterone levels were measured before and after 60-min exposure to restraint stress. SART stress itself did not alter the body temperature or serum corticosterone levels in mice. Acute restraint stress increased the body temperature and serum corticosterone levels, both responses being greater in SART-stressed mice than unstressed mice. The enhanced hyperthermic responses to acute restraint stress in SART-stressed mice were significantly attenuated by SR59230A, a β 3 adrenoceptor antagonist, but unaffected by diazepam, an anxiolytic, mifepristone, a glucocorticoid receptor antagonist, or indomethacin, a cyclooxygenase inhibitor. These results suggest that SART stress enhances the susceptibility of mice to acute restraint stress, characterized by increased hyperthermia and corticosterone secretion, and that the increased hyperthermic responses to acute stress might involve accelerated activation of sympathetic β 3 adrenoceptors, known to regulate non-shivering thermogenesis in the brown adipose tissue.

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Translational aspects of pharmacological research into anxiety disorders: The stress-induced hyperthermia (SIH) paradigm

Cited by 91 publications

References 249 publications

The age of anxiety: role of animal models of anxiolytic action in drug discovery

The age of anxiety: role of animal models of anxiolytic action in drug discovery

A Cycloartane Glycoside Derived from Actaea racemosa L. Modulates GABA_A Receptors and Induces Pronounced Sedation in Mice

Repeated Cold Stress Enhances the Acute Restraint Stress-Induced Hyperthermia in Mice

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Translational aspects of pharmacological research into anxiety disorders: The stress-induced hyperthermia (SIH) paradigm

Cited by 91 publications

References 249 publications

The age of anxiety: role of animal models of anxiolytic action in drug discovery

The age of anxiety: role of animal models of anxiolytic action in drug discovery

A Cycloartane Glycoside Derived from Actaea racemosa L. Modulates GABAA Receptors and Induces Pronounced Sedation in Mice

Repeated Cold Stress Enhances the Acute Restraint Stress-Induced Hyperthermia in Mice

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A Cycloartane Glycoside Derived from Actaea racemosa L. Modulates GABA_A Receptors and Induces Pronounced Sedation in Mice